Atypical Michaelis-Menten kinetics in cytochrome P450 enzymes: A focus on substrate inhibition.

Autor: Leow JWH; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore., Chan ECY; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore; Innovations in Food, Chemical and Drug Safety (IFCS), Agency for Science, Technology and Research (A*STAR) Program, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore. Electronic address: phaccye@nus.edu.sg.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2019 Nov; Vol. 169, pp. 113615. Date of Electronic Publication: 2019 Aug 21.
DOI: 10.1016/j.bcp.2019.08.017
Abstrakt: The widespread applications of the century-old Michaelis-Menten kinetics in the characterization of drug-metabolizing cytochrome P450 enzymes have persisted since their discovery in the 1950s. This is a concern given preceding reports of atypical Michaelis-Menten kinetics in substrates and effectors of cytochrome P450 enzymes which disprove previous notions that these phenomena exist purely as experimental artifacts while highlighting the neglected risk of errors when adopting inaccurate hyperbolic kinetic models for both in vitro-in vivo extrapolation and prediction of drug-drug interactions. This commentary summarizes the various types of atypical Michaelis-Menten kinetics, such as biphasic kinetics, homotropic and heterotropic cooperativity, with a special focus on substrate inhibition kinetics, the postulated mechanisms and models in the presence and absence of a xenobiotic inhibitor and roles in regulation of endogenous metabolism. Potential artifactual sources of atypical kinetics are also discussed.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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